Phase II Trial of Silymarin for Patients With Chronic Hepatitis C Who Have Failed Conventional Antiviral Treatment (SyNCH)

A Multicenter, Randomized, Double-masked, Placebo-controlled Phase II Study to Assess the Safety and Efficacy of a Standardized Orally Administered Silymarin Preparation (Legalon) for the Treatment of Patients With Chronic Hepatitis C Who Failed Conventional Antiviral Therapy

Silymarin (Legalon), also known as milk thistle, is an alternative medicine commonly found in health food and vitamin stores. People with liver disease sometimes use silymarin because it is thought to have liver protecting effects; however, this benefit has not been proven. The purpose of this research study is to determine the effectiveness of silymarin and assess the safety of different silymarin doses in patients with varying severity of liver disease compared to a placebo (lactose pill).

Eligible subjects will be randomized to treatment with placebo or one of two dosages of Legalon® 420 mg or 700 mg administered orally thrice daily. Investigators and subjects will be masked to treatment assignment. The study design includes a screening period during which patients will undergo full medical evaluation to verify protocol eligibility and a treatment period of 24 weeks during which time clinic visits and laboratory studies will be performed every 2-4 weeks to monitor for safety and efficacy of therapy. Subjects will continue to be followed for an additional 12 weeks after the completion of study medication to monitor for adverse events and investigate post-treatment outcomes. Participation in this research study requires the subject to travel to the clinic for at least 10 visits so recruitment will be limited to a geographically restricted area around participating clinical centers.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Other: Placebo; Drug: Silymarin; Drug: Silymarin

Detailed Description

This proposal is a phase II study that will evaluate the safety and efficacy of silymarin for the treatment of subjects with chronic hepatitis C who did not respond to conventional antiviral therapy. The primary objectives of this study are to assess the safety and adverse event profile of silymarin over a range of doses compared to placebo and to assess efficacy of silymarin in normalizing serum aminotransferase activity in patients with chronic hepatitis C. Secondary objectives are to characterize the effect of silymarin on serum levels of HCV RNA and to explore relationships between silymarin therapy and serum biomarkers of HCV hepatic disease activity (oxidative stress, apoptosis, and fibrogenesis).

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 00215
      • Beth Israel Deaconess Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age at least 18 years at screening.
• Serum HCV RNA above quantifiable level of detection by any assay after the end of previous therapy.
• ALT > 65 IU/L (i.e., approximately 1.5 X upper limit of normal) obtained during the screening period.
• Previous treatment with any interferon-based therapy without sustained virological response.
• Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of silymarin. Females of childbearing potential must be using two reliable forms of effective contraception during the study (while on drug and during follow-up).

Exclusion Criteria:

• Use of silymarin or other milk thistle preparations within 30 days prior to screening.
• Use of other antioxidants such as vitamin E, vitamin C, glutathione, alpha-tocopherol, or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations, and special teas) within 30 days prior to screening. A multivitamin at standard doses will be allowed.
• Use of silymarin or other antioxidants or non-prescribed complementary alternative medications (as above) during the screening period or patient unwilling to refrain from taking these medications through completion of the study.
• Any antiviral therapy within 6 months prior to screening visit.
• Known allergy/sensitivity to milk thistle or its preparations.
• Evidence of poorly-controlled diabetes (defined as HbA1c > 8% in patients with diabetes).
• Use of warfarin, metronidazole or acetaminophen (greater than two grams per day) within 30 days of screening.
• Lactose intolerance defined as patient reported inability to tolerate milk products.
• Previous liver biopsy that demonstrated presence of moderate to severe steatosis or evidence of steatohepatitis.
• Positive test for anti-HIV or HBsAg within 5 years of screening.
• Average alcohol consumption of more than one drink or equivalent (>12 grams) per day or more than two (2) drinks on any one day over the 30 days prior to screening. Patients who met either criterion more than 30 days ago must have consumed a monthly average of 12 grams or less per day of alcohol for at least six months prior to screening.
• History of other chronic liver disease, including metabolic diseases, documented by appropriate test(s).
• Women with ongoing pregnancy or breast-feeding, or contemplating pregnancy.
• Serum creatinine level 2.0 mg/dL or greater at screening or CrCl ≤ 60cc/min, or currently on dialysis. The creatinine clearance (CrCl) will be calculated according to Cockcroft-Gault.
• Evidence of drug abuse within 6 months prior to screening or during the screening period.
• Evidence of decompensated liver disease defined as any of the following: serum albumin <3.2 g/dl, total bilirubin > 1.5 mg/dl, or PT/INR > 1.3 times normal at screening, or history or presence of ascites or encephalopathy, or bleeding from esophageal varices.
• History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease, coronary artery disease, or active gastrointestinal conditions that might interfere with drug absorption).
• History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hepatitis, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis) that could affect inflammatory biomarkers.
• History of solid organ or bone marrow transplantation.
• History of thyroid disease poorly controlled on prescribed medications.
• Use of oral steroids for more than 14 days within 30 days prior to screening.
• Participation in a research drug trial, exclusive of the SyNCH Phase I trial, within 6 months of enrollment.
• Inability or unwillingness to provide informed consent or abide by the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: 1; Placebo (lactose pill)	Other: Placebo; Placebo (5 pills, three times daily) for 24-week treatment period; Other Names: lactose pill
EXPERIMENTAL: 2; 700mg of Legalon (silymarin) three times daily	Drug: Silymarin; 700mg dose (5 pills, three times daily) for 24-week treatment period; Other Names: Legalon; milk thistle; Drug: Silymarin; 420mg dose (5 pills, three times daily) for 24-week treatment period; Other Names: Legalon; milk thistle
EXPERIMENTAL: 3; 420mg Legalon (silymarin) three times daily	Drug: Silymarin; 700mg dose (5 pills, three times daily) for 24-week treatment period; Other Names: Legalon; milk thistle; Drug: Silymarin; 420mg dose (5 pills, three times daily) for 24-week treatment period; Other Names: Legalon; milk thistle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Efficacy - whether or not serum ALT (mg/dl) is less than or equal to 45 IU/L (approximate normal range) or achieves at least 50% decline to less than 65 IU/L (approximately 1.5 times the upper limit of normal)	24-week treatment period
Safety - occurence of a dose-limiting toxicity	24-week treatment period

Secondary Outcome Measures

Outcome Measure	Time Frame
Adherence - summary of missed dose information obtained from patient diaries and dose counts	24 week treatment period
Biomarkers - the following relationships will be explored: dose and change in biomarkers, changes in biomarkers and rate of treatment success, change in biomarkers and rate of toxicity	24 week treatment period

Collaborators and Investigators

• Sponsor: National Center for Complementary and Integrative Health (NCCIH)
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Pennsylvania; Beth Israel Deaconess Medical Center; University of Pittsburgh; University of North Carolina, Chapel Hill; Thomas Jefferson University

Publications and helpful links

General Publications

• Reddy KR, Belle SH, Fried MW, Afdhal N, Navarro VJ, Hawke RL, Wahed AS, Doo E, Meyers CM; SyNCH Study Group. Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C. Clin Trials. 2012 Feb;9(1):102-12. doi: 10.1177/1740774511427064. Epub 2011 Nov 4.
• Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, Doo E, Meyers CM, Reddy KR; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. 2012 Jul 18;308(3):274-82. doi: 10.1001/jama.2012.8265.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (ACTUAL): January 1, 2011
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: May 15, 2008
• First Submitted That Met QC Criteria: May 15, 2008
• First Posted (ESTIMATE): May 20, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): March 18, 2013
• Last Update Submitted That Met QC Criteria: March 11, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: hepatitis C
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; Silymarin
• Other Study ID Numbers: U01AT003566 (NIH); IND 74,887